Efficient synthesis of novel jolkinolides and related derivatives starting from stevioside

Article abstract of DOI:10.1055/s-0031-1289293

Jolkinolides are naturally occurring tetracyclic diterpene from Euphorbia genus, which exhibit promising antitumor and other biological activity. Efficient syntheses of the 19-carboxy derivative of jolkinolide A and 19-hydroxyjolkinolide E have been accom

Full text of DOI:10.1055/s-0031-1289293

PAPER
3807
Efficient Synthesis of Novel Jolkinolides and Related Derivatives Starting
from Stevioside
Synthesis of
N
o
i
vel Jol
a
n
d
Related D
-
e
rivative
Y
s
ong Shi,a Jia-Qiang Wu,a Da-Yong Zhang,*a Yang-Chang Wu,b Wei-Yi Hua,a Xiao-Ming Wu*a
a
Center of Drug Discovery, College of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang Road, Nanjing 210009,
P. R. of China
Fax +86(25)83271307; E-mail: zhangdayong@cpu.edu.cn; E-mail: xmwu@cpu.edu.cn
Graduate Institute of Pharmaceutical Chemistry, College of Pharmacy, China Medical University, 91 Hsueh-Shih Road,
Taichung 40402, Taiwan
b
Received 11 July 2011; revised 20 September 2011
starting material, and developed a facile access to obtain
the target compounds (Scheme 1).
Abstract: Jolkinolides are naturally occurring tetracyclic diterpene
from Euphorbia genus, which exhibit promising antitumor and oth-
er biological activity. Efficient syntheses of the 19-carboxy deriva-
tive of jolkinolide A and 19-hydroxyjolkinolide E have been
accomplished in 13 steps with a total yield of 7.8% starting from the
easily available and low-cost sweetener stevioside, and some relat-
ed derivatives have also been synthesized.
Stevioside was hydrolyzed by a literature method7 to give
the steviol 4 in 70% yield (Scheme 2). Selective esterifi-
cation of 4 with chloromethyl methyl ether and N,N-diiso-
propylethylamine gave 5 in good yield (95%).8 Treatment
of 5 with selenium oxide and tert-butyl hydroperoxide led
to 6 (85%), which was subsequently oxidized with pyri-
dinium dichromate to afford 7 (75%).9 Ozone oxidation of
7 at –78 °C gave a mixture of 8 and 9.10 In normal ozonol-
ysis, only the double bond is cleaved, but during this reac-
tion, the C13–C16 and C15–C16 single bonds are both
cleaved. We proposed that the Criegee rearrangement
may have occurred.11
Key words: jolkinolides, Euphorbiaceae, stevioside, antitumor
Natural products are interesting sources of novel leading
compounds for the design of new drugs. ‘Lang-du’ serv-
ing as a kind of traditional Chinese medicine with various
biological activity was first described ~2,000 years ago. It
is the root of dried Euphorbia Fischeriana Steud (Euphor-
biaceae) and has been used in folk medicine for the treat-
ment of cancer, edema, inflammation, tuberculosis, and
ascites.1 Many scientists have paid close attention to the
active components of this herb, and many investigations
have reported that it mainly contained diterpenoids, triter-
penoids, tannins, and steroids.2 Abietane lactone-type
diterpenoids are the main components in Euphorbia ge-
nus, and this kind of carbon skeleton is commonly tetra-
cyclic with a g-ylidenbutenolide functionality in ring D
and some oxidation function groups in ring C, such as an
unsaturated bond and hydroxy, carbonyl, and epoxy
groups.3 Jolkinolides A, B, D, and E (Figure 1) are the
representative compounds of the abietane lactones and ex-
hibit significant antitumor activity with IC50 values rang-
ing from 7.1 nM to 0.5 mM.4 It was reported that the
molecular target and mode of action of abietane lactones
were inhibition the activation of NF-kB signaling path-
way and JAK/STAT signaling pathway, and induced apo-
ptosis of tumor cells.5
As shown in Scheme 3, during the ozone oxidation pro-
cess, the C16–C17 double bond of 7 was transformed to
1,2,3-trioxacyclopentane intermediate I, which then rear-
ranged to the more stable ozonide intermediate III, and
further rearrangement of intermediate III with the loss of
methanal provided 8, some of which was decarboxylated
to afford compound 9. We attempted to modify the reac-
tion conditions (e.g. time, temperature, ozone quantity) to
increase the yield of 9, but the products of ozonolysis
were still a mixture of 8 and 9. Next we examined the
transformation of 8 to 9, several conventional decarboxy-
lation methods [e.g., Pb(OAc)4, NaIO4] were attempted,
but failed. However, when we treated 8 with pyridinium
O
O
O
12
O
C
16
O
B
D
O
17
11
15
14
20
13
1
4
9
2
3
10
5
8
H
H
H
O
A
7
Katsumura et al.6 carried out the total synthesis of ( )-
jolkinolides A, B, and E starting from 10-(methoxycarbo-
nyl)-b-ionone through a synthetic route of almost twenty
reaction steps and bearing a low yield to obtain the target
compounds. Herein, we simply modified the synthetic
route using easily available and low-cost stevioside as our
H 6
18
19 A
B
O
O
O
O
H
H
OH
H
H
H
H
D
SYNTHESIS 2011, No. 23, pp 3807–3814
x
x.
x
x
.
2
0
1
1
E
Advanced online publication: 20.10.2011
DOI: 10.1055/s-0031-1289293; Art ID: H68611SS
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Structures of jolkinolides A, B, D, and E

3808
L.-Y. Shi et al.
PAPER
O
O
O
O
β-glu-β-glu(2 1)
O
O
O
H
O
H
H
H
O
H
O
H
H
H
H
COO-β-glu
stevioside
COOR
COOR
OR
3a: R = H
3b: R = MOM
1a: R = H
2a: R = Bn
2b: R = Me
2c: R = MOM
1b: R = Bn
1c: R = Me
1d: R = MOM
Scheme 1 Synthetic strategy for the preparation of novel jolkinolides and related derivatives
dichromate at room temperature, it gave the desired com- sodium hydride to afford lactone 1d. Then, deprotection
pound 9. We also attempted ozone oxidation of 6 to give of MOM ester 1d with 10% hydrochloric acid in tetrahy-
compound 9 directly, but because of the extremely poor drofuran at room temperature gave the acid 1a.
solubility of 6 in various solvents, the yield of oxidation
products was very low. At this point, since compound 7
was very soluble in all kinds of solvents, we attempted the
ozone oxidation of 7 and found the reaction was smoothly
The synthetic strategy for preparation of 19-hydroxyjolki-
nolide E is shown in Scheme 4, treatment 4 with excess
chloromethyl methyl ether provided 15. Reduction of 15
with lithium aluminum hydride in refluxing tetrahydrofu-
accomplished in good yield. Decarboxylation of 9 with
ran led to 16, which was acetylated with acetic anhydride
lead tetraacetate in refluxing benzene provided enone 10
and gave acetate 17 in high yield (95%). Using the same
(60%).12 Epoxidation of 10 with hydrogen peroxide af-
preparative procedures en route to 10, acetate 17 was
forded the C8–C14 epoxy 11 in moderate yield (61%).
transformed to enone 23. Deprotection of 23 with 10% hy-
Treatment of 11 with tert-butoxybis(dimethylami-
drochloric acid in refluxing methanol gave C15-hydroxy
enone 24 in high yield (96%). Chloromethyl methyl ether
no)methane in N,N-dimethylformamide gave 12 (90%).
Then, using Wasserman oxidation, we transformed 12
was used to protect the C15-hydroxy of 24 to afford com-
into 13 in moderate yield (70%).13 Esterification of 13
pound 25 in 97% yield.14 Application of Rubottom oxida-
with 2-(diethoxyphosphoryl)propanoic acid in the pres-
tion and treatment of 25 with lithium diisopropylamide
and trimethylsilyl chloride gave a silyl enol ether, which
was treated with 3-chloroperbenzoic acid and followed by
ence of 4-(dimethylamino)pyridine and N,N¢-dicyclohex-
ylcarbodiimide provided 14, which was treated with
O
β-glu-β-glu(2
1)
H
OH
O
OH
OH
OH
OH
c
d
b
a
H
H
H
H
H
H
H
H
H
COO-β-glu
COOMOM
COOH
COOMOM
COOMOM
7
4
5
6
stevioside
O
O
O
O
COOH
e
f
h
g
H
H
H
COOH
H
O
H
H
H
H
O
COOMOM
COOMOM
COOMOM
COOMOM
11
8
9
10
O
O
N
O
O
OR
O
O
j
i
l
m
H
H
O
H
O
H
O
H
O
H
H
H
COOMOM
12
COOH
COOMOM
COOMOM
13: R = H
14: R = COCH(Me)PO(OEt)2
1d
1a
k
Scheme 2 Reagents and conditions: (a) NaIO4, KOH, H2O, 70%; (b) MOMCl, DIPEA, DMF, r.t., 95%; (c) SeO2, t-BuOOH, THF, r.t.;
(d) PDC, DMF, r.t., 75%; (e) O3, CH2Cl2, –78 °C; (f) PDC, DMF, 77%; (g) Cu(OAc)2·H2O, Pb(OAc)4, pyridine, benzene, reflux, 60%; (h) 30%
H2O2, 6 M NaOH, MeOH, r.t., 61%; (i) t-BuOCH(NMe)2, DMF, 80 °C; (j) O2, tetraphenylporphine, CH2Cl2, iodo-halogen lamp, –78 °C, 70%;
(k) 2-(diethoxyphosphoryl)propanoic acid, DCC, DMAP, CH2Cl2, r.t., 61%; (l) 60% NaH, THF, r.t., 82%; (m) 10% HCl, THF, H2O, r.t., 97%.
Synthesis 2011, No. 23, 3807–3814 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Jolkinolides and Related Derivatives
3809
OH
OH
OH
O
O
O
O
O
O
ozone
H
H
H
H
H
H
O
O
O
H
COOMOM
7
COOMOM
COOMOM
II
I
O
O
O
O
O
COOH
O
[O]
H
H
H
COOH
H
H
H
O
O
COOMOM
COOMOM
COOMOM
HCHO
CO2
9
8
III
Scheme 3 Ozone oxidation rearrangement of 7
desilylation with tetrabutylammonium fluoride to afford ture,16 20-CH3 is a-orientated, so we could identify the
b-hydroxy ketone 26 overall in 51% yield.15 We attempt- configuration of the C12-hydroxy of 26 as b-orientated.
ed to use the same method with 23 as the substrate to ob- Deprotection of 3b (10% HCl in THF–MeOH, r.t.) gave
tain the b-hydroxy ketone directly, but this was 3a. The physical data of compound 3a is in agreement
unsuccessful, we thought that perhaps excess n-butyllith- with the naturally occurring compound 19-hydroxyjolkin-
ium may have decomposed the C15-acetyl protecting olide E, which was isolated from the roots of Phlogacan-
group. Esterification of 26 with 2-(diethoxyphosphor- thus curviflorus.18
yl)propanoic acid gave 27, which was treated with sodium
Several related derivatives of jolkinolide A, B were pre-
pared from compound 1a as outlined in Scheme 5. Ester-
hydride to afford 3b.17
From the NOESY spectrum of target compound 3b ification of 1a with halogenated compounds, such as
(Figure 2), H12 (dH = 4.87) shows correlations to 20-CH3 benzyl chloride provided 1b. Epoxidation of 1b with 3-
(dH = 0.93), which suggests that C12-hydroxy and 20-CH3 chloroperbenzoic acid gave 2a (70%).The NOESY spec-
bear the opposite configuration. According to the litera- trum of 2a (Figure 2) was used to identify the configura-
OMOM
OH
OMOM
b
OMOM
c
OMOM
d
a
e
H
H
H
H
H
H
H
H
H
H
OH
OAc
COOH
COOMOM
15
OH
OAc
18
16
17
4
OMOM
O
OH
O
O
O
O
g
i
f
h
COOH
H
H
H
H
H
H
H
H
H
H
COOH
O
OAc
OAc
OAc
OAc
OAc
19
23
21
22
20
O
O
OR
O
O
O
O
k
O
H
H
H
H
l
n
j
o
H
H
H
H
H
H
H
H
H
CH2OMOM
OMOM
CH2OH
OH
OMOM
26: R = H
24
25
3b
m
3a
27: R = COCH(Me)PO(OEt)2
Scheme 4 Reagents and conditions: (a) MOMCl, DIPEA, DMF, r.t., 97%; (b) LiAlH4, THF, reflux, 86%; (c) Ac2O, DMAP, THF, r.t., 95%;
(d) SeO2, t-BuOOH, THF, r.t., 85%; (e) PDC, DMF, r.t., 75%; (f) 10% HCl, THF, H2O, r.t., 97%; (g) O3, CH2Cl2, –78 °C, 88%; (h) PDC, DMF,
77%; (i) Pb(OAc)4, benzene, pyridine, reflux, 60%; (j) 10% HCl, MeOH, reflux, 96%; (k) MOMCl, DIPEA, CH2Cl2, reflux, 97%; (l) 1. LDA,
TMSCl, THF, –78 °C; 2. 85% MCPBA, CH2Cl2, –40 °C, 51%; (m) 2-(diethoxyphosphoryl)propanoic acid, DCC, DMAP, CH2Cl2, r.t.; (n) 60%
NaH, THF, r.t.; 90%; (o) 10% HCl, THF, H2O, r.t., 97%.
Synthesis 2011, No. 23, 3807–3814 © Thieme Stuttgart · New York

3810
L.-Y. Shi et al.
PAPER
and the mixture was allowed to stir at r.t. for 2 h. The mixture was
neutralized with 10% HCl and extracted with EtOAc. The EtOAc
layer was washed with brine, dried (anhyd Na2SO4), filtered, and
evaporated to dryness. The residue was purified by flash chroma-
tography (silica gel, PE–EtOAc, 6:1) to give 5 (2.2 g, 95%) as a
white amorphous solid; mp 234–236 °C.
tion of the C8–C14 epoxy and C11–C12 epoxy groups,
while both H11 (dH = 3.65 ppm) and H14 (dH = 3.15 ppm)
show correlations to 20-CH3 (dH = 0.54 ppm). It suggests
that H11, H14, and 20-CH3 bear the same configuration.
As 20-CH3 is a-orientated, therefore H11, H14 are also a-
orientated, while the C8–C14 and C11–C12 epoxy groups
are b-orientated. Compounds, such as 1c, 2b, and 2c were
also prepared with the same procedure.
IR (KBr): 3406, 2979, 2949, 2837, 1732, 1715, 1655, 1461, 1445,
1375, 1337, 1251, 1167, 1141, 1130, 1102, 1078, 1009, 938, 927,
906, 886, 771 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.22 (d, J = 5.98 Hz, 1 H), 5.14 (d,
J = 5.98 Hz, 1 H), 4.93 (s, 1 H), 4.77 (s, 1 H), 3.45 (s, 3 H), 2.13–
2.18 (m, 2 H), 1.99–2.07 (m, 3 H), 1.68–1.99 (m, 6 H), 1.35–1.70
(m, 6 H), 1.22–1.25 (d, J = 11.1 Hz, 1 H), 1.17 (s, 3 H), 0.91–1.06
(m, 3 H), 0.84 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 176.6, 155.6, 102.7, 90.2, 79.7,
57.6, 56.6, 53.5, 47.2, 46.5, 43.8, 41.3, 41.1, 40.4, 39.1, 39.02, 37.6,
28.5, 21.6, 20.1, 18.8, 15.3.
O
O
O
O
O
O
O
b
a
H
H
H
O
O
O
H
H
H
COOH
COOR
COOR
MS (ESI): m/z = 385 [M + Na]+.
HRMS: m/z [M]+ calcd for C22H34O4: 362.2457; found; 362.2473.
1b, R = Bn
1c, R = Me
1d, R = MOM
1a
2a, R = Bn
2b, R = Me
2c, R = MOM
Scheme 5 Reagents and conditions: (a) RX, DMF, r.t., 93%; (b)
85% MCPBA, CH2Cl2, r.t., 70%.
Methoxymethyl ent-13-Hydroxy-15-oxokaur-16-en-18-oate (7)
To a soln of 6 (1.5 g, 3.97 mmol) in DMF (15 mL) was added PDC
(1.64 g, 4.37 mmol). The mixture was allowed to stir at r.t. for 3 h
and then neutralized with 10% HCl, and extracted with EtOAc. The
EtOAc layer was washed with brine, dried (anhyd Na2SO4), filtered,
and evaporated to dryness. The residue was purified by flash chro-
matography (silica gel, PE–EtOAc, 3:1) to give 7 (1.05 g, 75%) as
a white amorphous solid; mp 187–189 °C.
H
H
O
H
H3C
O
O
BnOOC
O
CH3
H
CH3
2a
IR (KBr): 3451, 2953, 2923, 2868, 1733, 1717, 1651, 1464, 1378,
1325, 1283, 1172, 1133, 1072, 1043, 961, 946, 935, 765 cm–1.
H
H
1H NMR (300 MHz, CDCl3): d = 6.02 (s, 1 H), 5.44 (s, 1 H), 5.27
(d, J = 5.98 Hz, 1 H), 5.18 (d, J = 5.98 Hz, 1 H), 3.49 (s, 3 H), 2.51
(d, J = 11.21 Hz, 1 H), 2.21 (d, J = 14.3 Hz, 1 H), 1.74–2.04 (m, 9
H), 1.40–1.51 (m, 4 H), 1.24 (s, 3 H), 1.17–1.21 (m, 2 H), 1.04–1.05
(m, 1 H), 0.96 (s, 3 H).
H3C
O
O
CH3
MOMOH2C
H
CH3
H
3b
13C NMR (75 MHz, CDCl3): d = 208.5, 176.7, 151.4, 114.9, 90.4,
76.7, 57.8, 55.9, 55.0, 50.1, 44.5, 44.0, 40.0, 39.7, 39.0, 37.6, 32.8,
28.7, 20.6, 20.0, 18.7, 15.5.
MS (ESI): m/z = 399 [M + Na]+.
HRMS: m/z [M]+ calcd for C22H32O5: 376.2250; found: 376.2257.
Figure 2 Key NOESY correlations of 2a and 3b
In summary, the syntheses of the 19-carboxy-derivative of
jolkinolide A 1a and 19-hydroxyjolkinolide E (3a) have
been accomplished in 13 steps with an overall yield of
7.8% Some related derivatives, such as 1b–d, 2a–c, 3b
have also been synthesized. Since stevioside is an easily
available and low-cost material, this preparation serves a
practical access to jolkinolides and related tetracyclic
diterpenoids, which are biologically active molecules
with pharmaceutical potential as antitumor and anti-in-
flammatory agents. Further structural modification and
biological evaluation are ongoing, and the results will be
reported in due course.
Methoxymethyl ent-8-Carboxy-13-oxopodocarpan-15-oate (9)
To a soln of 7 (2 g, 5.32 mmol) in CH2Cl2 (30 mL), the mixture was
subjected to O3 for 30 min before the addition of Et3N (1.5 mL,
10.39 mmol) at –78 °C. The mixture was stirred and allowed to
warm to r.t. over 3 h and then neutralized with 10% HCl, washed
with brine, dried (anhyd Na2SO4), filtered, and evaporated to dry-
ness. The resulting 1:1 mixture of 8 and 9 was treated with PDC (2
g, 5.32 mmol) in DMF (20 mL) at r.t. over 2 h and then neutralized
with 10% HCl, washed with brine, dried (anhyd Na2SO4), filtered,
and evaporated to dryness. The residue was purified by flash chro-
matography (silica gel, PE–EtOAc, 2:1) to give 9 as a white amor-
phous solid; mp 119–121 °C.
1H and 13C NMR spectra were recorded at 300 MHz and 75 MHz,
respectively; relative to internal TMS standard. LRMS and HRMS
were recorded in ESI mode. IR spectra were recorded either on neat
samples (KBr disks) or as thin film. The melting points of the com-
pounds were measured on a Kofler-type Reichert Thermovar micro
hot stage microscope and were uncorrected. Petroleum ether = PE.
IR (KBr): 3386, 3026, 2985, 2937, 2849, 2819, 1717, 1463, 1446,
1375, 1348, 1337, 1283, 1207, 1184, 1135, 1091, 1062, 1030, 992,
954, 934, 913, 809, 788 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.28 (d, J = 5.94 Hz, 1 H), 5.18 (d,
J = 5.94 Hz, 1 H), 3.49 (s, 3 H), 2.58 (m, 1 H), 2.23 (d, J = 13.15
Hz, 2 H), 1.69–2.05 (m, 11 H), 1.48–1.53 (m, 1 H), 1.25 (s, 5 H),
1.03 (m, 1 H), 0.92 (s, 4 H).
Methoxymethyl ent-13-Hydroxykaur-16-en-18-oate (5); Typi-
cal Procedure
To a soln of 4 (2 g, 6.29 mmol) in DMF (20 mL) were added
MOMCl (0.5 mL, 6.22 mmol) and DIPEA (1.8 mL, 10.88 mmol),
13C NMR (75 MHz, CDCl3): d = 176.7, 90.5, 57.9, 55.7, 44.0, 43.4,
39.8, 37.6, 33.2, 28.7, 20.1, 19.6, 18.8, 15.0.
Synthesis 2011, No. 23, 3807–3814 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Jolkinolides and Related Derivatives
3811
MS (ESI): m/z = 389 [M + Na]+.
fied by flash chromatography (silica gel, PE–EtOAc, 4:1) to give 13
(0.38 g, 70%) as a white amorphous solid; mp 123–125 °C.
HRMS: m/z [M]+ calcd for C20H30O6: 366.2042; found: 366.2048.
IR (KBr): 3426, 2937, 2850, 1727, 1678, 1452, 1407, 1275, 1261,
1229, 1164, 1132, 1077, 931, 861, 764, 743 cm–1.
Methoxymethyl ent-13-Oxopodocarp-8(14)-en-15-oate (10)
To a soln of 9 (1.3 g, 3.4 mmol) in anhyd benzene (30 mL) were
added Cu(OAc)2·H2O (0.1 g, 0.4 mmol) and pyridine (2 mL, 25.3
mmol); the mixture was purged with N2 for 15 min. After the addi-
tion of Pb(OAc)4 (4.5 g, 10.14 mmol), the soln was stirred at r.t. in
the dark for 1 h and then refluxed for 1 h. The soln was then filtered
through a pad of silica gel under vacuum, the mixture was neutral-
ized with 10% HCl, and the organic layer was washed with brine,
dried (anhyd Na2SO4), filtered, and evaporated to dryness. The res-
idue was purified by flash chromatography (silica gel, PE–EtOAc,
6:1) to give 10 (0.57 g, 60%) as a colorless oily product.
1H NMR (300 MHz, CDCl3): d = 5.76 (d, J = 5.67 Hz, 1 H), 5.27 (d,
J = 1.67 Hz, 1 H), 5.15 (d, J = 1.67 Hz, 1 H), 3.44 (s, 3 H), 3.39 (s,
1 H), 2.64 (d, J = 5.64 Hz, 1 H), 2.02–2.12 (m, 5 H), 1.78–1.81 (m,
2 H), 1.41–1.58 (m, 3 H), 1.29 (s, 3 H), 1.08–1.17 (m, 2 H), 0.60 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 191.8, 176.2, 145.6, 112.9, 90.6,
61.7, 61.1, 57.9, 54.2, 50.6, 44.6, 41.5, 39.9, 37.6, 33.4, 29.6, 28.8,
22.3, 19.1, 13.8.
MS (ESI): m/z = 373 [M + Na]+.
HRMS: m/z [M]+ calcd for C19H26O6: 350.1729; found: 350.1741.
IR (film): 2955, 1728, 1667, 1466, 1366, 1258, 1236, 1172, 1136,
1078, 1027, 932 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.88 (s, 1 H), 5.24 (d, J = 5.97 Hz,
2 H), 3.47 (s, 3 H), 1.40–2.58 (m, 16 H), 1.29 (s, 3 H), 1.11–1.12
(m, 1 H), 0.71 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 199.4, 176.3, 164.4, 125.5, 90.4,
57.7, 55.0, 50.4, 44.3, 39.9, 39.3, 37.7, 36.4, 36.2, 28.8, 23.5, 20.5,
19.3, 14.2.
MS (ESI): m/z = 321 [M + H]+.
HRMS: m/z [M]+ calcd for C19H28O4: 320.1988; found: 320.1986.
19-(Methoxymethoxy)-19-oxojolkinolide A (1d)
To a soln of 13 (0.14 g, 0.34 mmol) in CH2Cl2 (10 mL) were added
2-(diethoxyphosphoryl)propanoic acid (0.22 g, 1.04 mmol), DMAP
(20 mg, 0.16 mmol), and DCC (0.14 g, 0.68 mmol); the mixture was
stirred at r.t. for 1 h. The mixture was neutralized with 10% HCl and
extracted with EtOAc. The organic layer was washed with sat.
NaHCO3 and brine, dried (Na2SO4), filtered, and evaporated to dry-
ness. The residue was purified by flash chromatography (silica gel,
PE–EtOAc, 1:1) to give 14 (0.12 g, 61%) as a white amorphous sol-
id. To a soln of 14 (0.12 g, 0.28 mmol) in anhyd THF (10 mL) was
added 60% NaH at 0 °C, the mixture was stirred at r.t. for 3 h. The
mixture was diluted with sat. NH4Cl and extracted with EtOAc. The
organic layer was washed with sat. NaHCO3 and brine, and dried
(Na2SO4), and then purified by flash chromatography (silica gel,
PE–EtOAc, 3:1) to give 1d (0.072 g, 82%) as a white amorphous
solid; mp194–196 °C.
Methoxymethyl ent-8b,14b-Epoxy-13-oxopodocarpan-15-oate
(11)
To a soln of 10 (1 g, 2.73 mmol) in MeOH (20 mL) were added
dropwise 6 M NaOH (1 mL) and 30% H2O2 (2 mL) at 0 °C; the mix-
ture was stirred for 6 h at r.t. Then the mixture was neutralized with
10% HCl and extracted with EtOAc, dried (anhyd Na2SO4), filtered,
and evaporated to dryness. The residue was purified by flash chro-
matography (silica gel, PE–EtOAc, 9:1) to give 11 (0.64 g, 61%) as
a white needles; mp 89–91 °C.
IR (KBr): 2938, 2855, 1769, 1728, 1655, 1466, 1381, 1275, 1260,
1227, 1128, 1077, 939, 765, 750 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.47 (d, J = 5.3 Hz, 1 H), 5.27 (d,
J = 2.93 Hz, 1 H), 5.15 (d, J = 2.93 Hz, 1 H), 3.74 (s, 1 H), 3.47 (s,
3 H), 2.66 (d, J = 5.3 Hz, 1 H), 2.20 (m, 1 H), 2.06 (s, 3 H), 2.00–
2.15 (m, 3 H), 1.79–1.85 (m, 2 H), 1.57–1.66 (m, 2 H), 1.34–1.46
(m, 2 H), 1.30 (s, 3 H), 1.09–1.18 (m, 1 H), 0.59 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 176.2, 170.4, 146.6, 144.8, 125.5,
103.6, 90.6, 61.0, 58.0, 54.4, 54.0, 51.0, 44.6, 41.8, 40.0, 37.6, 34.6,
22.2, 28.9, 19.2, 14.2, 8.2.
IR (KBr): 3427, 2954, 2867, 1723, 1695, 1450, 1229, 1144, 935,
778, 735 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.28 (d, J = 5.97 Hz, 1 H), 5.14 (d,
J = 5.97 Hz, 1 H), 3.43 (s, 3 H), 3.18 (s, 1 H), 2.45–2.39 (m, 1 H),
2.13–2.23 (m, 4 H), 1.80–1.96 (m, 6 H), 1.30–1.50 (m, 4 H), 1.27–
1.30 (m, 2 H), 1.12 (s, 3 H), 1.06–1.10 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 208.1, 176.1, 90.3, 66.5, 62.9, 57.7,
54.9, 47.5, 43.9, 39.9, 39.8, 37.6, 35.2, 33.3, 28.7, 22.7, 18.9, 16.3,
14.7.
MS (ESI): m/z = 411 [M + Na]+.
HRMS: m/z [M]+ calcd for C22H28O6: 388.1886; found: 388.1898.
MS (ESI): m/z = 354 [M + NH4]+.
19-Hydroxy-19-oxojolkinolide A (1a)
HRMS: m/z [M]+ calcd for C19H28O5: 336.1937; found: 336.1947.
To a soln of 1d (50 mg, 0.14 mmol) in THF (5.00 mL) was added
10% HCl (2 mL). The mixture was stirred at r.t. for 3 h. The mixture
was neutralized with sat. NaHCO3 soln, and then extracted with
EtOAc. The EtOAc layer was washed with brine, dried (anhyd
Na2SO4), filtered, and evaporated to dryness. The residue was puri-
fied by flash chromatography (silica gel, PE–EtOAc, 2:1) to give 1
(43 mg, 97%) as a white amorphous solid; mp 213–216 °C.
Methoxymethyl 12-[(Dimethylamino)methylene]-8b,14b-epoxy-
13-oxopodocarpan-15-oate (12)
To a soln of 11 (0.67 g, 1.75 mmol) in DMF (3 mL) was added t-
BuOCH(NMe)2 (0.78 mL, 3.21 mmol) and stirred for 1 h at 120 °C.
The mixture was neutralized with sat. NaHCO3 soln, and then ex-
tracted with EtOAc, the EtOAc layer was washed with brine, and
dried (anhyd Na2SO4). Evaporation of the organic solvent gave the
crude oil 12 (0.70 g), which was used for the next reaction without
further purification.
IR (KBr): 3452, 2931, 2851, 1769, 1693, 1448, 1401, 1381, 1275,
1260, 1213, 1077, 1045, 880, 850, 764, 746 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.47 (d, J = 5.27 Hz, 1 H), 3.74 (s,
1 H), 2.66 (d, J = 5.14 Hz, 1 H), 2.26–2.32 (m, 2 H), 2.07–2.13 (m,
3 H), 2.06 (s, 3 H), 1.77–1.85 (m, 3 H), 1.51–1.64 (m, 3 H), 1.38–
1.43 (m, 1 H), 1.32 (s, 3 H), 0.65 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 183.2, 170.5, 147.5, 144.7, 125.4,
103.7, 61.0, 54.3, 54.0, 50.9, 44.2, 41.8, 39.9, 37.4, 34.5, 29.6, 28.9,
22.1, 19.1, 14.3, 8.6.
Methoxymethyl ent-8b,14b-Epoxy-12-hydroxy-13-oxopodo-
carp-11-en-15-oate (13)
To a soln of 12 (0.6 g, 1.37 mmol) in CH2Cl2 (30 mL) was added
tetraphenylporphine (2 mg, 0.003 mmol); the mixture was irradiat-
ed with a 300-W iodo-halogen lamp while O2 was bubbling for 0.5
h at –78 °C. Then the mixture was concentrated in vacuo and puri-
Synthesis 2011, No. 23, 3807–3814 © Thieme Stuttgart · New York

3812
L.-Y. Shi et al.
PAPER
MS (ESI): m/z = 345 [M + H]+.
ent-18-Acetoxy-13-hydroxy-15-oxokaurene (20)
To a soln of 19 (0.5 g, 1.24 mmol) in THF (10 mL) was added 10%
HCl (2 mL); the mixture was stirred for 30 min. The mixture was
neutralized with sat. NaHCO3 soln, and then extracted with EtOAc,
the EtOAc layer was washed with brine, dried (anhyd Na2SO4), fil-
tered, and evaporated to dryness. The residue was purified by flash
chromatography (silica gel, PE–EtOAc, 3:1) to give 20 (0.43 g,
97%) as a white amorphous solid; mp191–193 °C.
HRMS: m/z [M]+ calcd for C20H24O5: 344.1624; found: 344.1632.
Methoxymethyl ent-13-(Methoxymethoxy)kauren-18-oate (15)
Following the typical procedure for 5, treatment of 4 (2.0 g, 6.29
mmol) gave 15 as a colorless oily product (1.24 mg, 97%).
IR (KBr): 2986, 2944, 2847, 1730, 1462, 1446, 1130, 1078, 1046,
930, 764, 749 cm–1.
IR (KBr): 3488, 2947, 2932, 2865, 1723, 1643, 1482, 1443, 1392,
1372, 1285, 1250, 1160, 1109, 1096, 1037, 980, 964, 951, 930 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.30 (d, J = 5.97 Hz, 1 H), 5.15 (d,
J = 5.97 Hz, 1 H), 4.91 (s, 1 H), 4.86 (s, 1 H), 4.81 (d, J = 7.03 Hz,
1 H), 4.59 (d, J = 7.03 Hz, 1 H), 3.49 (s, 3 H), 3.36 (s, 3 H), 2.01–
2.23 (m, 4 H), 1.73–1.89 (m, 6 H), 1.52–1.70 (m, 7 H), 1.22 (s, 3 H),
0.96–1.09 (m, 3 H), 0.87 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 176.6, 152.3, 103.5, 91.3, 90.1,
85.1, 57.6, 56.7, 54.9, 53.5, 47.5, 43.8, 42.9, 41.4, 41.3, 40.4, 39.1,
38.5, 37.7, 28.6, 21.6, 19.8, 18.9, 15.4.
1H NMR (300 MHz, CDCl3): d = 6.03 (s, 1 H), 5.43 (s, 1 H), 4.20
(d, J = 11 Hz, 1 H), 3.88 (d, J = 11 Hz, 1 H), 2.51 (d, J = 11 Hz, 1
H), 2.05 (s, 3 H), 1.96–2.04 (m, 2 H), 1.67–1.90 (m, 6 H), 1.52–1.63
(m, 1 H), 1.30–1.50 (m, 5 H), 1.21–1.27 (m, 1 H), 1.09 (s, 4 H),
0.99–1.07 (m, 1 H), 0.97 (s, 3 H), 0.79–0.84 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 208.5, 171.4, 151.3, 114.9, 66.8,
55.6, 54.9, 51.2, 44.4, 39.6, 39.3, 39.1, 36.8, 35.9, 32.9, 27.3, 20.8,
20.4, 18.5, 17.7.
MS (ESI): m/z = 407 [M + H]+.
HRMS: m/z [M]+ calcd for C24H38O5: 406.2719; found: 406.2730.
MS (ESI): m/z = 383 [M + Na]+.
HRMS: m/z [M]+ calcd for C22H32O4: 360.2301; found: 360.2303.
ent-18-Hydroxy-13-(methoxymethoxy)kaurene (16)
To a soln of 15 (0.6 g, 1.46 mmol) in anhyd THF (15 mL) was added
LiAlH4 (0.2 g, 5.26 mmol) at 0 °C and the mixture was refluxed for
40 min. The mixture was diluted with sat. NH4Cl and extracted with
EtOAc. The organic layer was washed with brine, dried (anhyd
Na2SO4), filtered, and evaporated to dryness. The residue was puri-
fied by flash chromatography (silica gel, PE–EtOAc, 1:1) to give 16
(0.44 g, 86%) as a white amorphous solid; mp 153–155 °C.
ent-15-Hydroxypodocarp-8(14)-en-13-one (24)
To a soln of 23 (200 mg, 0.48 mmol) in MeOH (15 mL) was added
10% HCl (3 mL); the mixture was stirred and refluxed for 30 min.
The mixture was neutralized with sat. NaHCO3 soln, and then ex-
tracted with EtOAc, the EtOAc layer was washed with brine, dried
(anhyd Na2SO4), filtered, and evaporated to dryness. The residue
was purified by flash chromatography (silica gel, PE–EtOAc, 3:1)
to give 24 (165 mg, 96%) as a white amorphous solid; mp 183–186
°C.
IR (KBr): 3527, 3439, 2997, 2923, 2868, 2842, 1664, 1631, 1448,
1384, 1204, 1085, 1075, 1019, 971, 880 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.89 (s, 1 H), 4.84 (s, 1 H), 4.80
(d, J = 7.07 Hz, 1 H), 4.58 (d, J = 7.07 Hz, 1 H), 3.71 (d, J = 10.9
Hz, 1 H), 3.40 (d, J = 10.9 Hz, 1 H), 3.36 (s, 3 H), 1.99–2.15 (m, 3
H), 1.75–1.87 (m, 4 H), 1.31–1.67 (m, 10 H), 0.99 (s, 3 H), 0.94 (s,
3 H), 0.72–0.91 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 152.4, 103.6, 91.5, 85.4, 65.1, 56.7,
55.1, 54.8, 47.7, 43.1, 41.8, 41.5, 40.3, 38.9, 38.7, 38.6, 35.5, 27.0,
20.3, 19.8, 18.1, 17.9.
IR (KBr): 3361, 2928, 2869, 1734, 1656, 1608, 1453, 1375, 1261,
1059, 1028, 749, 649 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.87 (s, 1 H), 3.81 (d, J = 10.7 Hz,
1 H), 3.47 (d, J = 10.7 Hz, 1 H), 2.51–2.53 (m, 1 H), 2.38–2.43 (m,
1 H), 2.21–2.27 (m, 1 H), 2.08–2.20 (m, 1 H), 2.00–2.08 (m, 2 H),
1.74–1.92 (m, 4 H), 1.46–1.57 (m, 3 H), 1.33–1.38 (m, 1 H), 1.03
(s, 3 H), 0.93–1.01 (m, 2 H), 0.78 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 200.0, 165.4, 125.8, 64.9, 54.9,
51.6, 39.2, 38.9, 38.6, 36.6, 35.9, 35.2, 27.0, 21.9, 20.6, 18.4, 16.3.
MS (ESI): m/z = 371 [M + Na]+.
HRMS: m/z [M]+ calcd for C22H36O3: 348.2644; found: 348.2664.
MS (ESI): m/z = 263 [M + H]+.
HRMS: m/z [M]+ calcd for C17H26O2: 262.1933; found: 262.1935.
ent-18-Acetoxy-15-hydroxy-13-(methoxymethoxy)kaurene (18)
To a soln of 17 (0.7 g, 1.79 mmol) in THF (15 mL) were added SeO2
(0.12 g, 1.08 mmol) and t-BuOOH (2 mL); the mixture was stirred
at r.t. for 3 h. The mixture was diluted with distilled H2O and ex-
tracted with EtOAc, the EtOAc layer was washed with brine, dried
(anhyd Na2SO4), filtered, and evaporated to dryness. The residue
was purified by flash chromatography (silica gel, PE–EtOAc, 4:1)
to give 18 (0.62 g, 85%) as a colorless oily product.
ent-15-(Methoxymethoxy)podocarp-8(14)-en-13-one (25)
To a soln of 24 (1.65 g, 6.29 mmol) in CH2Cl2 (20 mL) was added
MOMCl (0.5 mL, 6.22 mmol) and DIPEA (2 mL); the mixture was
allowed to stir at 60 °C for 2 h. The mixture was neutralized with
10% HCl, extracted with CH2Cl2. The organic layer was washed
with brine, and dried (Na2SO4), filtered, and evaporated to dryness.
The residue was purified by flash chromatography (silica gel, PE–
EtOAc, 6:1) to give 25 (1.85 g, 97%) as a colorless oily product.
IR (film): 3465, 2935, 2871, 1738, 1461, 1390, 1371, 1461, 1390,
1371, 1240, 1151, 1110, 1098, 1034, 996, 972, 907 cm–1.
IR (film): 2929, 2882, 1671, 1616, 1446, 1275, 1259, 1145, 1106,
1046, 750 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.32 (s, 1 H), 5.17 (s, 1 H), 4.81
(d, J = 7.06 Hz, 1 H), 4.83 (d, J = 7.06 Hz, 1 H), 4.21 (d, J = 11.04
Hz, 1 H), 3.90 (d, J = 11.04 Hz, 1 H), 3.74 (s, 1 H), 3.38 (s, 3 H),
2.09 (s, 1 H), 2.04 (s, 3 H), 1.90–2.00 (m, 4 H), 1.78–1.89 (m, 3 H),
1.67–1.78 (m, 5 H), 1.37–1.66 (m, 6 H), 1.05 (s, 3 H), 0.96 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.2, 157.2, 108.9, 91.4, 84.2,
81.1, 66.9, 56.4, 55.1, 52.9, 45.6, 40.0, 39.3, 38.9, 38.4, 36.8, 36.1,
35.3, 27.3, 20.8, 19.4, 19.3, 17.9, 17.8.
1H NMR (300 MHz, CDCl3): d = 5.87 (s, 1 H), 4.58 (s, 2 H), 3.63
(d, J = 9.3 Hz, 1 H), 3.36 (d, J = 9.3 Hz, 1 H), 3.34 (s, 3 H), 2.50–
2.57 (m, 1 H), 2.35–2.43 (m, 1 H), 2.15–2.26 (m, 2 H), 1.98–2.10
(m, 2 H), 1.70–1.97 (m, 4 H), 1.42–1.58 (m, 3 H), 1.07–1.34 (m, 3
H), 1.04 (s, 3 H), 0.80 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 199.6, 165.0, 127.4, 96.7, 70.7,
55.0, 54.9, 51.6, 39.3, 38.9, 37.6, 36.7, 36.0, 35.9, 27.8, 22.0, 20.6,
18.4, 16.3.
MS (ESI): m/z = 429 [M + Na]+.
HRMS: m/z [M]+ calcd for C24H38O5: 406.2719; found: 406.2717.
MS (ESI): m/z = 307 [M + H]+.
HRMS: m/z [M]+ calcd for C19H30O3: 307.2268; found: 307.2281.
Synthesis 2011, No. 23, 3807–3814 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Jolkinolides and Related Derivatives
3813
ent-12-Hydroxy-15-(methoxymethoxy)podocarp-8(14)-en-13-
one (26)
IR (KBr): 3437, 2923, 2850, 1748, 1666, 1599, 1453, 1301, 1275,
1261, 1089, 1021, 959, 764, 745 cm–1.
To a soln of i-Pr2NH (0.47 mL, 3.5 mmol) in THF (2 mL) was added
1.3 M BuLi in hexane soln (2.2 mL, 3.5 mmol) at –78 °C and the
mixture was stirred for 30 min at the same temperature. To the gen-
erated LDA soln was added a soln of 25 (0.2 g, 0.65 mmol) in THF
(5 mL) at –78 °C and the mixture was stirred for 1 h at the same tem-
perature. To the above mixture was added TMSCl (0.6 mL, 3.4
mmol) and the mixture was stirred at r.t. for 2 h. The mixture was
diluted with EtOAc and the organic layer was washed with sat.
NaHCO3 and brine, dried (Na2SO4). Evaporation of the organic sol-
vent gave crude oily product, which was used for the next reaction
without further purification. To a soln of the oily product in CH2Cl2
(20 mL) was added 85% MCPBA (0.45 g, 2.2 mmol) at –40 °C and
the mixture was stirred for 3 h at the same temperature. The mixture
was added TBAF (0.8 g, 2.8 mmol) at r.t. and the mixture was
stirred for 2 h. The mixture was diluted with sat. NaHCO3 and
CH2Cl2 and the organic layer was washed with 10% HCl and brine,
and dried (Na2SO4), filtered, and evaporated to dryness. The residue
was purified by flash chromatography (silica gel, PE–EtOAc, 2:1)
to give 26 (107 mg, 51%) as a colorless oily product.
1H NMR (300 MHz, CDCl3): d = 6.26 (s, 1 H), 4.85 (d, J = 4.8 Hz,
1 H), 3.77 (d, J = 10.8 Hz, 1 H), 3.46 (d, J = 10.8 Hz, 1 H), 2.47–
2.61 (m, 2 H), 2.16–2.23 (m, 1 H), 1.89–1.99 (m, 2 H), 1.84 (s, 3 H),
1.52–1.60 (m, 2 H), 1.31–1.49 (m, 2 H), 1.16–1.26 (m, 5 H), 1.02
(s, 3 H), 0.92 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 156.0, 151.6, 114.1, 75.9, 65.1,
56.1, 51.9, 41.5, 39.6, 37.5, 35.6, 29.7, 27.6, 27.3, 23.9, 18.8, 17.7,
14.1, 8.2.
MS (ESI): m/z = 339 [M + Na]+.
HRMS: m/z [M]+ calcd for C20H28O3: 316.2038; found: 316.2045.
19-(Benzyloxy)-19-oxojolkinolide A (1b); Typical Procedure
To a soln of 1a (100 mg, 0.29 mmol) in DMF (7 mL) were added
BnCl (0.06 mL, 0.43 mmol) and K2CO3 (80 mg, 0.58 mmol); the
mixture was stirred at r.t. for 4 h. The mixture was neutralized with
10% HCl, and then extracted with EtOAc, the EtOAc layer was
washed with brine, dried (Na2SO4), filtered, and evaporated to dry-
ness. The residue was purified by flash chromatography (silica gel,
PE–EtOAc, 6:1) to give 1b (117 mg, 93%) as a white amorphous
solid; mp 149–151 °C.
IR (film): 3427, 2929, 2873, 1727, 1678, 1454, 1363, 1275, 1260,
1227, 1106, 1045, 965, 750, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.91 (s, 1 H), 4.58 (s, 1 H), 4.31
(m, 1 H), 3.58 (d, J = 9.3 Hz, 1 H), 3.35 (d, J = 9.3 Hz, 1 H), 3.34
(s, 3 H), 2.48–2.54 (m, 2 H), 2.18–2.29 (m, 2 H), 1.98–2.02 (m, 2
H), 1.79–1.90 (m, 2 H), 1.47–1.61 (m, 3 H), 1.23–1.36 (m, 2 H),
1.47–1.61 (m, 3 H), 1.04 (s, 3 H), 1.00 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 199.7, 167.0, 121.5, 96.7, 70.4,
69.1, 55.7, 55.1, 51.4, 42.1, 39.8, 37.8, 37.4, 36.5, 29.3, 28.1, 24.0,
18.8, 17.2.
[a]D20 +62.262 (c 8.946, MeOH).
IR (KBr): 2936, 2853, 1769, 1720, 1661, 1496, 1454, 1381, 1275,
1260, 1226, 1207, 1155, 1132, 1036, 1014, 971, 883, 850, 766, 761,
750, 745, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.47 (m, 5 H), 5.53 (d,
J = 5.3 Hz, 1 H), 5.25 (d, J = 12.4 Hz, 1 H), 5.09 (d, J = 12.4 Hz, 1
H), 3.79 (s, 1 H), 2.72 (d, J = 5.3 Hz, 1 H), 2.38 (m, 1 H), 2.19–2.23
(m, 1 H), 2.15 (s, 3 H), 2.01–2.14 (m, 2 H), 1.85 (m, 2 H), 1.63–1.71
(m, 2 H), 1.51–1.63 (m, 1 H), 1.37 (s, 3 H), 1.34–1.41 (m, 1 H),
1.15–1.26 (m, 1 H), 0.57 (s, 3 H).
MS (ESI): m/z = 345 [M + Na]+.
HRMS: m/z [M]+ calcd for C19H30O4: 322.2144; found: 322.2155.
13C NMR (75 MHz, CDCl3): d = 176.3, 170.4, 147.4, 144.8, 135.8,
128.5, 128.1, 128.0, 125.3, 103.7, 66.2, 61.0, 54.5, 54.0, 50.9, 44.3,
41.8, 40.0, 37.6, 34.5, 28.9, 22.2, 19.2, 14.1, 8.6.
MS (ESI): m/z = 435 [M + H]+.
HRMS: m/z [M]+ calcd for C27H30O5: 434.2093; found: 434.2108.
19-(Methoxymethoxy)jolkinolide E (3b)
Following the typical procedure for 1d, treatment of 26 (80 mg,
0.25 mmol) gave 3b as a white amorphous solid (73 mg, 82%); mp
189–191 °C.
[a]D20 +327.547 (c 3.96, MeOH).
IR (KBr): 2927, 2875, 1751, 1670, 1602, 1440, 1390, 1275, 1260,
1148, 1107, 1045, 1021, 962, 912, 763, 746 cm–1.
19-(Benzyloxy)-19-oxojolkinolide B (2a)
To a soln of 1b (30 mg, 0.069 mmol) in CH2Cl2 (7 mL) was added
85% MCPBA and the mixture was stirred at r.t. for 6 h. The mixture
was diluted with ice-water and extracted with EtOAc. The organic
layer was washed with sat. NaHCO3 and brine, dried (Na2SO4), fil-
tered, and evaporated to dryness. The residue was purified by flash
chromatography (silica gel, PE–EtOAc, 2:1) to give 2a (21 mg,
70%) as a white amorphous solid; mp 149–151 °C.
1H NMR (300 MHz, CDCl3): d = 6.26 (s, 1 H), 4.87 (d, J = 4.8 Hz,
1 H), 4.57 (s, 2 H), 3.59 (d, J = 9.4 Hz, 1 H), 3.33 (s, 3 H), 3.32 (d,
J = 9.4 Hz, 1 H), 2.48–2.61 (m, 2 H), 2.11–2.22 (m, 2 H), 1.90 (s, 3
H), 1.83–1.97 (m, 3 H), 1.38–1.56 (m, 5 H), 1.20–1.31 (m, 2 H),
1.02 (s, 3 H), 0.88 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 175.2, 156.0, 151.7, 116.3, 114.0,
96.7, 77.4, 77.0, 76.6, 75.9, 70.4, 56.1, 55.1, 52.0, 41.5, 39.6, 37.9,
37.5, 36.3, 29.7, 28.2, 27.5, 24.0, 18.8, 17.7, 8.2.
[a]D25 +115.108 (c 2.22, MeOH).
IR (KBr): 3427, 2944, 2849, 1776, 1720, 1458, 1384, 1316, 1261,
1231, 1171, 1147, 1098, 1046, 1010, 965, 877, 750, 736, 696 cm–1.
MS (ESI): m/z = 361 [M + H]+.
1H NMR (300 MHz, CDCl3): d = 7.30–7.36 (m, 5 H), 5.12 (d,
J = 12.5 Hz, 1 H), 5.06 (d, J = 12.5 Hz, 1 H), 3.98 (s, 1 H), 3.64 (s,
1 H), 2.27–2.29 (m, 2 H), 2.04–2.11 (m, 4 H), 1.98–1.91 (m, 3 H),
1.76–1.80 (m, 1 H), 1.55–1.59 (m, 1 H), 1.41–1.44 (m, 1 H), 1.29–
1.36 (m, 2 H), 1.26 (s, 3 H), 1.09–1.15 (m, 1 H), 0.54 (s, 3 H).
13C NMR(75 MHz, CDCl3): d = 176.1, 169.4, 148.3, 135.7, 130.2,
128.5, 128.2, 85.0, 66.3, 65.8, 60.8, 54.8, 54.5, 47.1, 44.1, 39.5,
39.2, 37.5, 35.9, 29.6, 28.9, 22.3, 19.2, 14.0, 8.6.
HRMS: m/z [M]+ calcd for C22H32O4: 360.2301; found: 360.2306.
19-Hydroxyjolkinolide E (3a)
To a soln of 3b (30 mg, 0.083 mmol) in THF (10 mL) were added
10% HCl (2 mL); the mixture was stirred at r.t. for 3 h. The mixture
was neutralized with sat. NaHCO3 soln, and then extracted with
EtOAc, the EtOAc layer was washed with brine, dried (anhyd
Na2SO4), filtered, and evaporated to dryness. The residue was puri-
fied by flash chromatography (silica gel, PE–EtOAc, 2:1) to give 3a
(25 mg, 97%) as a white amorphous solid; mp 198–201 °C.
MS (ESI): m/z = 473 [M + Na]+.
HRMS: m/z [M]+ calcd for C27H30O6: 450.2042; found: 450.2063.
Synthesis 2011, No. 23, 3807–3814 © Thieme Stuttgart · New York

3814
L.-Y. Shi et al.
PAPER
(7) Ogawa, T.; Nozaki, M.; Matsui, M. Tetrahedron 1980, 36,
2641.
Acknowledgement
This program was supported by grant from National Natural Sci-
ence Foundation of China (No.30973607 and No.81172934) and
the ‘Six Talent Peak’ Foundation of Jiangsu Province of China (No.
Y092003) and the Research and Innovation Plan for graduate of
Jiangsu Province of China (No. CX10B-371Z) for financial
assistance.
(8) (a) Cui, Y.-M.; Yasutomi, E.; Otani, Y.; Yoshinaga, T.; Ido,
K.; Sawada, K.; Ohwada, T. Bioorg. Med. Chem. Lett. 2008,
18, 5197. (b) Singh, S. B.; Ondeyka, J. G.; Liu, W.; Chen, S.;
Chen, T. S.; Li, X.; Bouffard, A.; Dropinski, J.; Jones, A. B.;
McCormick, S.; Hayes, N.; Wang, J.; Sharma, N.; MacNaul,
K.; Hernandez, M.; Chao, Y.-S.; Baffic, J.; Lam, M.-H.;
Burton, C.; Sparrow, C. P.; Menke, J. G. Bioorg. Med.
Chem. Lett. 2005, 15, 2824.
References and Notes
(9) Blay, G.; Garcia, B.; Molina, E.; Pedro, J. R. Tetrahedron
2007, 63, 9621.
(10) Terai, T.; Ren, H.; Mori, G.; Yashihito, Y.; Hayashi, T.
Chem. Pharm. Bull. 2002, 50, 1007.
(1) (a) Che, C.-T.; Zhou, T.-X.; Ma, Q.-G.; Qin, G.-W.;
Williams, I.-D.; Wu, H.-M.; Shi, Z.-S. Phytochemistry 1999,
52, 117. (b) Sutthivaiyakit, S.; Thapsut, M.;
(11) Bailey, P. S. Chem. Rev. 1958, 58, 925.
(12) (a) McMurry, J. E.; Blaszczak, L. C. J. Org. Chem. 1974, 39,
2217. (b) Schultz, A. G.; Wang, A. J. Org. Chem. 1996, 61,
4857.
(13) Wasserman, H. H.; Ives, J. L. J. Am. Chem. Soc. 1976, 98,
7868.
Prachayasittikul, V. Phytochemistry 2000, 53, 947.
(c) Wang, Y.-B.; Huang, R.; Wang, H.-B.; Jin, H.-Z.; Lou,
L.-G.; Qin, G.-W. J. Nat. Prod. 2006, 69, 967.
(2) (a) Shi, Y. P.; He, Z. J.; Jia, J. Z. Nat. Prod. Res. Dev. 1999,
11, 85. (b) Su, X.-L.; Lin, R.-C.; Wong, S.-K.; Tsui, S.-K.;
Kwan, S.-Y. Phytochem. Anal. 2003, 14, 40.
(14) (a) Jiang, B.; Shi, H.-P.; Tian, W.-S.; Zhou, W.-S.
Tetrahedron 2008, 64, 469. (b) Furber, M.; Mander, L. N.;
Patrick, G. L. J. Org. Chem. 1990, 55, 4860.
(15) (a) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R.
Tetrahedron Lett. 1974, 15, 4319. (b) Rubottom, G. M.;
Gruber, J. M.; Boeckman, R. K. Jr.; Ramaiah, M.; Medwid,
J. B. Tetrahedron Lett. 1978, 19, 4603.
(16) Mosettig, E.; Beglinger, U.; Dolder, F.; Lichti, H.; Quitt, P.;
Waters, J. A. J. Am. Chem. Soc. 1963, 85, 2305.
(17) Miyake, T.; Kigoshi, H.; Akita, H. Tetrahedron: Asymmetry
2007, 18, 2915.
(3) (a) Zhang, D. Y.; Shi, L. Y.; Wu, X. M. Chin. J. Org. Chem.
2009, 29, 188. (b) Lai, A. R.; Cambie, R. C.; Rutledge, P. S.;
Woogate, P. D. Phytochemistry 1990, 29, 2239. (c) Luo,
H.-Y.; Wang, A.-Q. Can. J. Physiol. Pharmacol. 2006, 84,
959. (d) Yamaguchi, K.; Uemura, D.; Tsuji, T.; Kondo, K.
Biosci. Biotechnol. Biochem. 1994, 58, 1749.
(4) Shi, H.-M.; Williams, I. D.; Sung, H. Y.; Zhu, H.-X.; Ip, N.
Y.; Min, Z.-D. Planta Med. 2005, 71, 349.
(5) (a) Yan, S.-S.; Li, Y.; Wang, Y.; Shen, S.-S.; Gu, Y.; Wang,
H.-B.; Qin, G.-W.; Yu, Q. Mol. Cancer Ther. 2008, 7, 1523.
(b) Wang, Y.; Ma, X.; Yan, S.; Shen, S.; Zhu, H.; Gu, Y.;
Wang, H.; Qin, G.; Yu, Q. Cancer. Res. 2009, 69, 7302.
(6) Katsumura, S.; Kimura, A.; Isoe, S. Tetrahedron 1989, 45,
1337.
(18) Lai, G.-F.; Wang, X.-Y.; Wang, Y.-F.; Cao, J.-X.; Luo, S.-
D.; Ju, P. Helv. Chim. Acta 2009, 92, 470.
Synthesis 2011, No. 23, 3807–3814 © Thieme Stuttgart · New York